News

 |  Publications
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Key Findings From Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014

Drug Metab Dispos. 2016 Jan; 44(1); 83-101.
Published online 2015 Sep 30

Abstract

Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmax ratio ≥2 or ≤0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ≥5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations.

 |  Publications
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Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Drug Metab Dispos. 2015 Nov; 43(11); 1823-37.
Published online 2015 Aug 21

Abstract

Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms “PBPK” and “physiologically based pharmacokinetic model” to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

 |  Publications
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Organ Impairment-Drug-Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs

CPT Pharmacometrics Syst Pharmacol. 2015 Aug; 4(8); 489-94.
Published online 2015 Jul 14

Abstract

The organ impairment and drug-drug interaction (OI-DDI) database is the first rigorously assembled database of pharmacokinetic drug exposure data from publicly available renal and hepatic impairment studies presented together with the maximum change in drug exposure from drug interaction inhibition studies. The database was used to conduct a systematic comparison of the effect of renal/hepatic impairment and pharmacologic inhibition on drug exposure. Additional applications are feasible with the public availability of this database.

 |  Events

DIDB Team at the 18th International Conference on Drug-Drug Interactions

The DIDB team will be exhibiting at the upcoming 18th International Conference on Drug-Drug Interactions in Seattle on June 29-July 1, 2014, and will contribute to the scientific program with two presentations:

* Critical Review of the 2014-2015 Literature (Dr. Sophie Argon)

* New Molecular Entities Approved by FDA in 2014: Review of In Vitro and In Vivo Data (Dr. Jingjing Yu)

Dr. Ragueneau-Majlessi will be chairing the session entitled “NDA and Literature Update” on June 29th.

 |  News

Dr. Ragueneau-Majlessi to present at the upcoming AAPS Meeting

Dr. Isabelle Ragueneau-Majlessi, Clinical Professor and Director of the DIDB Program, is an invited speaker at the session entitled “Overcoming potential setbacks? Prediction of Drug-Drug interactions via Computational Modeling“, taking place on Wednesday November 5th (7:00-8:30am) at the AAPS Meeting in San Diego. She will be presenting on “Indexing and Curating Drug-Drug Interaction Data: experience of the University of Washington Drug Interaction Database”.

 |  News

DIDB Team to exhibit at the upcoming ISSX/JSSX Meeting – San Francisco 10/19-10/23, 2014

Please visit the DIDB Team at Booth #408 during this year’s ISSX/JSSX Meeting to be held in San Francisco October 19 -23, 2014.

Also, please come to the following poster presentations:

  • P94 – ASSESSMENT OF THE IMPACT OF RENAL OR HEPATIC IMPAIRMENT VS PHARMACOLOGIC INHIBTION ON SYSTEMIC EXPOSURE OF DRUGS (Cathy Yeung, Makiko Kusama, Huixia Zhang, Isabelle Ragueneau-Majlessi, Sophie Argon, Li Li, Peter Chang, Ping Zhao, Lei Zhang, Kenta Yoshida, Issam Zineh, Yuichi Sugiyama, Shiew-Mei Huang).
  • Monday October 20
  • Presented by Authors: 1:15 – 2:00 pm  (Dr. Cathy Yeung)
  • P173 – DRUG DISPOSITION AND DRUG-DRUG INTERACTION DATA IN 2013 FDA NEW DRUG APPLICATIONS: A SYSTEMATIC REVIEW (Jingjing Yu and Isabelle Ragueneau-Majlessi).
  • Monday October 20
  • Presented by Authors: 4:30-5:15 pm (Dr. Jingjing Yu)
  • P390 – USE OF IN VIVO DISPOSITION DATA TO DETERMINE CYP2D6 PROBE fm VALUES AND DEVELOP PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS TO PREDICT GENOTYPE DEPENDENT CYP2D6-MEDIATED DRUG-DRUG INTERACTIONS (Mariko Nakano, Jingjing Yu, Sophie Argon, Isabelle Ragueneau-Majlessi, Nina Isoherranen).
  • Tuesday October 21
  • Presented by Authors: 6:15-7:00 pm (Dr. Mariko Nakano)
 |  Publications
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Drug Disposition and Drug-Drug Interaction Data in 2013 FDA New Drug Applications: A Systematic Review

Drug Metab Dispos. 2014 Dec; 42(12); 1991-2001.
Published online 2014 Sep 30

Abstract

The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs’ disposition.

 |  Events

DIDB Team at the 17th International Conference on Drug-Drug Interactions

The DIDB team will be exhibiting at the 17th International Conference on Drug-Drug Interactions in Seattle on June 30-July 2, 2014, and will contribute to the scientific program with two presentations:

* Critical Review of the 2013-2014 Literature (Dr. Sophie Argon)

* New Molecular Entities Approved by FDA in 2013: Review of In Vitro and In Vivo Data (Dr. Jingjing Yu)

Dr. Ragueneau-Majlessi will be chairing the session entitled “NDA and Literature Update” on June 30th.

 |  New features

e-PKGene Version 2.0 released April 11th!

The DIDB program is pleased to announce the release of e-PKGene Version 2.0.

Please see this detailed description of the new features.

New features include:

  1. A new responsive design that works on phones and tablets.
  2. A set of new quantitative searches:

    • Users are now able to select a combination of factors (compounds, genes, ethnicities) to query for quantitative measurements. Tabular results are provided in % ∆ from the reference population’s measurements and provide both pharmacokinetic (PK) and pharmacodynamic (PD) data.
    • These results can be further refined by filtering individual columns by text or by a numerical range. Columns can also be reordered or hidden from view. With these tools, users can explore the initial result set and refine the data to their needs. The data then can be saved as a spreadsheet.
  3. New design for displaying full citation and NDA information:

    • For each study, all information has been condensed into a single, easy to understand table. Measurement data for the citation/NDA can be viewed in the same manner as the quantitative results query by clicking on the “% ∆ data” link in the description section.
    • At the top of the citation navigation menu, “PK”, “PD”, and “Side Effects” buttons are highlighted only if the citation contains data for it; one click on either button will hide the information which is not of interest.
      needs. The data then can be saved as a spreadsheet.
  4. Updated drug summaries